Oroshnik



Sept. 9, 1952 w. ORQSHNIK 2,610,137

2-AMINO-4-DIALKYLAMINOETHOXY-GMETHYLPYRIMIDINES Filed Nov. 7, 1950 2 SHEETS SHEET 1 Thai.

INVENTOR fiu/r/v U/PoJ/w/m BY 7Q ATTORNE 9, 1952 w. OROSHNIK 2,610,137

ZAMINO-4-DIALKYLAMINOETHOXY-6-METHYLPYRIMIDINES Filed Nov. 7, 1950 2 Sl-iEETS-SHEET 2 I a b BY I a b 9 ATTORNEY stances;

substanceslto stimulate contractions of the. uterus Patented Sept. 9, 1952 UNITED STATES PATENT :OFFIGE enivnnoemramvmmuonrnoxna "METHYLPYRIMIDINES William Croshnik, Plainfield, .N. J., assignor t odka Pharmaceutical Corporation, a corporation of New J ersey Application November '1, issas n u No. 1 9 4 5 6 2 .5 Claims. (01. Mile-256.51)

in which R and R are eachan aliphatic radical which may be normal propyl, isopropyl, secondary butyl, or normal butyl.

A number of derivatives of isocytosine have been prepared and studied 'forflvariou's pharmaceutical and medicinal usesbut itis .believed that the particular derivatives of isocytosine with which this invention is concernedarenewlsub- It is also believed theabilityrof these has not been known heretofore.

The derivatives of isocytosine which. embody this invention-may be used assuch to stimulate contractions of the uterus.

They may also be used as in the form of salts of theisocytosinederivatives with organic or inorganic acids and since the said derivatives are basic in character, they may be readily converted into. salts having substantially more solubility -in water than the free bases.

Salts such as the succinate, maleate, tartrate, lactate, fumarate and thelike are preferred, but salts of simple low-molecularweight aliphatic organic acids as well as salts of the free bases with inorganic acids, may be readi1y'..prepared from the free bases and are highly effective therapeutically.

The new and novel derivatives of isocytosine to which the present invention is directed have considerable value which renders their use as pharmaceutical products highly advantageous either alone or with known pharmacological products. The ability of these novel substances to stimulate contractions of the uterus has been shown by a number of experiments in which a salt of the isocytosine derivative was added to a bath of nutrient solution having astripof albino rat uterine tissue suspended therein. A continuous kymographic record was made 01 contractions ofthe uterinestrip'before andafter addition to the bath of a "salt of an'isocytosine derivative. Additional derivatives of 'isocytosine which are homologues or 2 amino 4 dialkylamin'oethoxy e methyl pyrimidines specifically mentioned before as hav ing therapeutic value'were'also teste'din the same way to determine their eifect on con'tractions'of the uterus." The sesquisuccinates of the following compounds weretest'efd for their pharmacological v property o'f stimulating contractions of the Figures 1.46' 'aieisym uterus 3 2 933 1 7". in lhy li m Compound II- Z -.a m'ino" lf vdiisopropylaminor ethoxy: 6 methylpyrinndine" Compound I 2 amino -4 -,di -n propylaminm Com und IllEZ e tinct-a di n hutylem neet iqs :16 t e ir h mm en 'lV'r'? gam n 4* et ylami ethoxypyrimidine Compound V-Z amino 4 n diethylamino hpx p r mid n hen, met py mi fi 1he following procedurewas employed in testing the effect of compounds I-VI on a rat uterus:

A female albino rat weighing from -300 mungrams was killed by a blowon the head and'the uterus was removed. A strip of the uterine tissue was suspended in a loll-cc. bath of an aerated Ringer-Lockesolution. Oneend ofthe uterine strip was maintained in a stationary position and the other end was attached to a lever which made contact with akymograph andcontinuously re- )c lrde con raction A e a hetperied M mrsion Lin the bath the strip of uterinetissue was contracting rhythmicallynnd normally, and atthis point'a sesguis u'ocinatefof an jisocytosine derivative tombs its eife'ct on contractior1s1of uterinel'tis" e wa-s added tc th'e bath. V i ,raphic records of contractionsof thestrip of u erine tissue before and after addition to the-bath or thecompound's'tofbe tested. Normal contractions are recorded in the figures up to the point designated a and at this time a portion of the compound to be tested was added to the bath. The portion of the figures between letters a and 2 represents a record of contractions after addition to the bath of the compound being tested. The letter 22 in the figures designates the time at which the bath containing the compound being tested was removed and rerespectively, to the bath. Figures 4, 5, and16;

show the effect of the addition of 10 milligrams of compounds IV, V, and VI, respectively, to the bath.

Figure 1 shows the addition of 10 milligrams of the sesquisuccinate salt of compound I to the bath produced a marked increase in amplitude of contractions and a very marked increase in tonus of the uterine muscular tissue. Frequency 4 of xylene. Twelve hundred parts of benzene were then added to the resulting sodium salt of di-n-butylaminoethanol. One hundred forty three parts of z-aminoi-chloro-6-methylpyrimidine were added to the above solution, and, during the addition, the solution was cooled sufficiently to maintain the temperature at 80 C.

After the addition was complete, the reaction mixture was refluxed for one hour and cooled and then 100 parts of water containing 10 parts of dissolved sodium hydroxide were added with stirring. At this point two layers were formed and the organic layer was decanted, dried over anhydrous potassium carbonate, and the solvents, benzene and xylene, were removed by dis tillation. The. residue in the distillation flask was distilled atv a temperature of 124-140 C. 'and a pressure of 0.001 mm. of mercury. One

of contractions was notincreased to any substantial degree. Figure 2 shows the addition of 10 milligrams of the sesquisuccinate salt of compound II to the bath produced a very marked increase in amplitude of contractions but practically no increase in tonus of the uterine muscular tissue. A substantial increase in the frequency of contractions was also produced. Figure 3 shows the addition of 5 milligrams of the sesquisuccinate salt of compound III to the bath produced a very marked increase in amplitude of contractions and tonus of the uterine muscular tissue, as well as a slight increase in frequency of contraction. Figures 4, 5, and 6 show only slight effects on the uterine muscular tissue result from the addition of the sesquisuccinate salts of compounds IV, V, and VI to the bath. Figure 4 shows the addition of 10 milligrams of the sesquisuccinate salt of compound'IV to the bath produced a slight decrease in amplitude of contractions, and Figures 5 and 6 show the addition of 10 milligrams of the sesquisuccinate salts of compounds V and VI, respectively, to the bath produced a slight increase in amplitude of contractions and a slight increase in tonus of the uterine muscular tissue.

Tonus is a natural property of muscle and is a measure of degree of contraction independent of external influences. The degree of contraction produced by a stimulant depends upon the level of tonus, and, therefore, some investigators have defined tonus as the resistance offered to 1 extension.

Amplitude may be defined as the height of a contraction wave measured from the base level to the peak of the wave; base level being the average lower level of the contractions.

Frequency is the number of contraction waves in a unit time period.

Derivatives of isocytosine such as 2-aminoldialkylaminoethoxy-fi-methylpyrimidines may be prepared by reacting 2-amino-4-chloro-G-meth-= ylpyrimidine with the sodium salt of a dialkylaminoethanol. The following is an example of the preparation of 2-amino-4-di-n-butylaminoethoxy-S-methylpyrimidine, in which the parts are given by weight. Twenty-five parts of sodium metal were slowly added to 200 parts of di-n-butylaminoethanol, dissolved in 500 parts hundred and eighty parts of 2-amino-4-di-nbutylaminoethoxy-S-methylpyrimidine were obtained and subsequently recrystallized from ether. The crystallineproduct. had a melting point of 51-52 C. The pure-compound is soluble in most organic compounds and insoluble in water. A water-soluble sesquisuccinate of the free base was prepared as follows; 5 grams of the base and 3.15 grams of succinic acid were dissolved in 30 cc. of hot acetone. A. white crystalline material precipitated on cooling this solution. The precipitate was removed by filtering andrecrystallize'd from acetone. The recrystallized material had a' melting point of 127128 C. The crystalline salt had the following formula:

What is. claimed is: 1. A compound having the structural formula in which R and R each represent an alkyl radical selected'from the group consisting of normal propyl, isopropyl, secondary. butyl, and: normal butyl radicals.

2. A compound according to claim 1 in which R and R, are each a normal propyl radical.

3. A compound according to claim 1 in which R and R are each a normal propyl radical.

4. A compound according to claim 1 in which R and R are each a secondary butyl radical.

5. A compound according to claim 1 in which R and R are each a normal butyl radical.

1 WILLIAM OROSHNIK.

' REFERENCES CITED The following references are of record in the file of this patent: I 7

Sutherland et al.: J. Org. Chem. 14, 235-238 (1949).

Braker et a1.:

J. Am. Chem. Soc. to, 3072-3078 (1947). 

1. A COMPOUND HAVING THE STRUCTURAL FORMULA 